The association of α5β1 integrin with tumor angiogenesis is well-established (see, e.g., U.S. Publ. Pat. Appl. U.S. 2002/0172675 A1, filed May 7, 1999, which is hereby incorporated by reference herein). α5β1 is a heterodimeric integrin that specifically binds the ligand fibronectin. α5β1 is expressed on the surface of endothelial cells and mediates adhesion to and migration toward fibronectin. The binding interaction between α5β1 and fibronectin has been shown to be important for tumor angiogenesis. Angiogenesis within a tumor begins when the release of one or more pro-angiogenic growth factors (e.g., FGF, VEGF, PDGF, etc.) locally activates the endothelial cells. These activated endothelial cells then form new blood vessels by binding, via their α5β1 integrin, to the fibronectin in the extracellular matrix. Anti-α5β1 antibodies have been shown to inhibit angiogenesis in in vivo tumor models (see, e.g., U.S. 2002/0172675 A1).
Anti-angiogenesis cancer therapy is based on inhibiting tumor vascularization and thereby preventing continued tumor growth and metastasis (for reviews see, e.g., Marx, “A Boost for Tumor Starvation,” Science 301, 452 (2003); Sato, “Molecular Diagnosis of Tumor Angiogenesis and Anti-Angiogenic Cancer Therapy,” Int. J. Clin. Oncol. 8, 200 (2003); Bissachi et al., “Anti-Angiogenesis and Angioprevention: Mechanisms, Problems and Perspectives,” Cancer Detec. Prev. 27, 229 (2003)). More than 60 anti-angiogenesis based therapeutics currently are in clinical development for cancer treatment. While in some cancers, it may be possible to “starve” a tumor by preventing its vascularization, current research shows that there are cancers that do not appear to be vulnerable to anti-angiogenesis treatment (see, Sato, supra). For example, the anti-VEGF antibody therapeutic, AVASTIN™ (bevacizumab) succeeded in clinical trials for colon cancer but not breast cancer (see, Marx, supra). In addition, anti-angiogenesis based therapeutic methods are not well-suited to early-stage treatment when the tumor vascularization process has not yet begun.
Due to its function in angiogenesis, the α5β1 integrin has been proposed as a therapeutic target for numerous diseases mediated by angiogenic processes including cancerous tumor growth. Chimeric and humanized antibodies to α5β1 have been developed that block specific binding to fibronectin. A chimeric α5β1 antibody, M200 (also known by its generic name, volociximab) has been shown to induce apoptosis of activated endothelial cells in vitro regardless of the growth factor stimulus.
Thus, there remains a need for cancer therapies and early-stage treatment methods capable of directly killing cancer cells before the tumor vascularization process even begins, or for when a targeted anti-angiogenesis therapy proves ineffective.